Atrial fibrillation (AF) is a serious public health problem because of its increasing prevalence in the aging population and its association with elevated risks of ischemic stroke, dementia, heart failure, and death. Recent evidence suggests that an increased stroke risk is also observed in patients with left atrial (LA) enlargement, even in the absence of AF, and that the vast majority of ischemic strokes are not temporally related to AF episodes. These observations raise the tantalizing question whether it is AF or the underlying LA substrate that causes the cardiovascular (CV) outcomes attributed to AF. This proposal will test our hypothesis: It is the abnormal LA substrate of impaired function and/or enlargement, and not AF per se, that is the principal driver of adverse outcomes currently attributed to AF, such as cerebral infarct and cognitive decline. To test this hypothesis, we will not only assess LA enlargement, but also impaired LA function, in relation to development of new MRI-defined brain infarcts and cognitive change, accounting for AF. We will leverage the extensive tests that were performed on Atherosclerosis Risk in Communities (ARIC) Study participants at visit 5 (V5, 2011-13) as baseline data: cognitive tests, 2D-echocardiograms (2DE), and brain MRI scans. We will measure LA function on 3,600 2DEs that were performed at V5 and leverage the data collected by 2 other ancillary studies at V6 and 7 (2016-19): (1) heart rhythm monitoring on 4,000 participants by Zio?XT Patch (R01HL126637), and (2) repeat brain MRI scans on 1,000 participants (R01AG05449). Cognitive tests will be repeated and mild cognitive impairment (MCI) and dementia will be adjudicated as part of the V6 and 7 exams. By measuring LA function from V5 2DEs and efficiently leveraging the data collected at V5 and from V6 and 7 ancillary studies, we will accomplish these specific aims: (1) Evaluate the prospective association of LA abnormality with new MRI cerebral infarcts, cognitive change, and incident MCI or dementia, with and without adjusting for AF; (2) Evaluate the prospective association of AF with new MRI cerebral infarcts, cognitive change, and incident MCI or dementia, with and without adjusting for LA abnormality; (3) Define mechanisms for AF-related cognitive decline by evaluating the associations of (a) LA abnormality or AF with longitudinal changes in specific brain MRI findings; (b) LA abnormality or AF with cognitive change, adjusting for clinical ischemic stroke, MRI cerebral infarcts, or other brain MRI abnormalities. If our hypothesis is confirmed, this project will have important public health and clinical impact. Our findings may (1) shift our attention to the atrial substrate as the principal driver of adverse outcomes, re-directing future efforts to discover novel strategies to prevent LA abnormality, in contrast to the current focus on rhythm control of established AF, and (2) motivate future clinical trials to test anticoagulation for patients with LA abnormality to prevent stroke. Ultimately, this project will underscore the importance of the underlying abnormal atrial substrate in understanding AF-related morbidities, and consequently advance the science and clinical practice of AF.